Most malaria drugs containing artemisinin-derivatives are currently not approved in ICH - and associated countries. As a result the documentation needed for the prequalification and the assessment thereof poses some special challenges. Most of these drugs for which an Expression of Interest for the Prequalification Procedure was invited, cannot be evaluated following either the normal procedures for generics or those procedures for innovators as described in current WHO recommendations. Therefore, a different approach had to be developed for the majority of applications.

Two main options for proving acceptable efficacy and safety of these Finished Pharmaceutical Products [FPP] exist:

1. Demonstrate bio-equivalence with an established, acceptable reference product. A suitable reference product has to be identified by the applicant and must be one that is acceptable to WHO assessors.

2. Provide direct evidence in support of the product’s efficacy and safety, which in most cases will be based on both of the following

• general information pertaining to the active ingredients pharmacologic properties, including toxicological, pharmacokinetic, and efficacy and safety data as published, and resulting from investigations with preparations different from the FPP applied for

• specific information emerging from clinical studies performed with the proposed product

This note applies to the second option. Ideally, the dossier of the application should follow the recommendations provided in the ICH guidance on the Common Technical Document (ICH CTD M4E) and other pertinent ICH guidelines. This may not always be possible or necessary in each case.

However, there are a few basic requirements which every FPP must meet in order to be further considered for the prequalification:

1. Complete list of all clinical trials performed with the proposed FPP (compare ICH CTD M4E, section 2.7.3.2 and 2.7.3.6 and tables 2.7.3.1 and 2)

2. If different galenical formulations of the FPP have been marketed or used in clinical trials, a galenical development history should be provided with clear identification of the respective formulations used in the trials included in the list (see 1.)

3. Basic pharmacokinetic characterisation of the FPP

4. Summary of Product Characteristics and Package Insert

5. Expert reports on pharmaco-toxicological and clinical evidence for the active ingredient as well as the FPP

All documentation, new or additional, provided with current or future Expressions of Interest will first be checked whether these basic requirements are fulfilled. If the basic requirements are not met then no assessment will be conducted on the clinical data. The applicant will be notified of the deficiencies. When the basic requirements are met an assessment of the data provided will commence and more comprehensive communications will be sent to the applicant as required.

Further comments regarding basic requirements:

Ad 1: The applicants should provide a complete list of all clinical trials (phase I, II and III) they are aware of and for which their product was used. It should be indicated whether the study was sponsored by the applicant. As a first step in the identification of studies not sponsored by the applicant, a consultation of the review of the Cochrane database may be useful: Artemisinin derivatives for treating uncomplicated malaria. (McIntosh HM, Olliaro P., In: The Cochrane Library, Issue 2, 2003 Oxford).

This list should be updated each time when substantial new information, i.e. new clinical studies with the FPP, is submitted

Existing full study reports and publications based on these studies should be submitted. If no study report or publication exists for any of the aforementioned clinical trials, the applicants should comment on reasons known to them and either confirm that they are not aware of any negative findings in unpublished trials or comment on all unreported and unpublished evidence.

Ad 2: If different galenical forms were manufactured in the development history of the product, then the applicant should provide a list in order to clearly identify the different forms used in the respective studies. If the applicant is not able to identify the specific galenical form (e.g. for an independently performed trial) then they should comment on which form was most likely used. It should be confirmed unambiguously if only one galenical formulation was ever used in humans.

Ad 3: In most cases, the most important part of the evidence about the pharmacokinetic properties of the active ingredient will come from the literature. However, at least some information about the pharmacokinetics/bioavailability of the FPP is absolutely necessary, too, in order to allow a judgement as to whether results from clinical trials with other FPPs can at least to a sufficient degree be extrapolated to the FPP applied for. This information may come from studies in healthy volunteers or in patients. In all cases the results will have to be discussed and compared to results from published studies in the Clinical Expert Report. The results from pharmacokinetic investigations must be described briefly in the SPC of the product.

Ad 4: The SPC and package insert should be specific with regard to the infections which can be reasonably treated with the FPP. In most cases the FPP will not be equally well suited for both uncomplicated and complicated malaria, or for all species of Plasmodia. Efforts should be made to keep the SPC up to date, especially with regard to safety-relevant information.

Ad 5: Expert reports will have to be updated - just like the list of all trials - as soon as new substantial information is added